Use-dependent block of cardiac late Na+ current by ranolazine

BACKGROUND Ranolazine is an antianginal drug that inhibits the cardiac late Na+ current (I-Na). The selectivity of ranolazine to block late IN, relative to peak I-Na at rapid heart rates has not been determined, but is potentially important to drug efficacy and safety. OBJECTIVE This study sought to quantify use-dependent block (UDB) of cardiac peak and late I-Na by ranolazine. METHODS Wild-type (WT) and long QT3 mutation R1623Q channels were expressed in HEK293 cells and studied using whole-cell patch-clamp technique. RESULTS Ranolazine (1 to 300 mu M) caused tonic (0.1 Hz) and UDB (1, 2, and 5 Hz) of WT and R1623Q peak I-Na. The IC50 values for block of WT and R1623Q peak I-Na at 0.1, 1, 2, and 5 Hz were 430, 260, 157, and 154 mu M, and 95, 77, 37, and 25 mu M, respectively. The IC50 values for block of R1623Q late I-Na at 0.1, 1, 2, and 5 Hz were 7.5, 7.3, 2.2, and 1.9 mu M, respectively. Ranolazine (10 mu M) caused a hyperpolarizing shift of WT and R16230 peak I-Na steady-state inactivation without affecting steady-state activation, suggesting that ranolazine interacts with inactivated states of the channels. Ranolazine (30 mu M) significantly slowed the recovery from inactivation of peak I-Na of both WT and R1623Q and bate I-Na of R1623Q. CONCLUSION Ranolazine slowed recovery of Late I-Na from inactivation and thus caused UDB of late I-Na. These data suggest that the effect of ranolazine to block late I-Na may be increased and the selectivity to block Late I-Na relative to peak I-Na may be retained during tachycardia.